The major objectives of this research proposal are: (1) to elucidate the physiology of (a) esophageal peristalsis and (b) lower esophageal sphincter (LES) tone and relaxation; (2) to identify the nature of the neurotransmitters involved in esophageal reflex activities; (3) to explore the pharmacology of esophageal body and LES; and (4) to arrive at a synthesis of structure-function relationships by complementing these studies with morphological investigations. These studies in the animal model will be extended to diseased tissues obtained at surgery from patients with esophageal disorders. We will use a number of different in vivo and in vitro systems to record membrane potentials by indirect (suction electrodes) and direct (single cell intracellular) methods, so as to learn about the nature of the neural reflexes in both intact animals as well as in muscle strips. These studies will also extend to the morphology and morphometry of the myenteric plexus, using our recently-developed rapid non-silver method and our technique of ganglionic isolation. An immunocytochemical approach will provide valuable histophysiological insights to supplement morphological findings. Ganglionic isolation will also be used to investigate ultrastructure with scanning and transmission electron microscopy of the myenteric plexus from various segments of the esophagus. Morphologic and physiologic correlations of neural control of esophageal function will thus be made. These studies will advance our understading of the physiology of esophageal motility and the pathophysiology of esophageal motor disorders. This understanding may provide avenues for rational treatment of these disorders. Moreover, lessons learned from these studies of the esophagus may have wider implications in physiology and pathophysiology of the autonomic nervous system, particularly that of the gastrointestinal tract.